Melatonin is known to most people simply as the hormone responsible for sleep. Produced by the pineal gland through a pathway inhibited by light, the release of melatonin helps entrain sleep to periods of darkness, and deficient secretion of melatonin is associated with insomnia and circadian rhythm disturbances. Yet, it might be surprising to discover that the pineal gland accounts for less than 1 percent of the body’s total secretion of melatonin and that the other more than 99 percent is not secreted in a manner at all dependent on light. Rather, the majority of the body’s melatonin is actually synthesized in the gastrointestinal tract (GI) tract, and its release is not circadian but rather occurs in response to eating.
The fact that the gastrointestinal tract synthesizes its own neurotransmitters, in quantities far exceeding their synthesis in the brain, has fascinated researchers and provides a theoretical rationale for exploring the gut-brain axis, explaining how diet and/or digestive function can be linked to changes in mood or behavior. Melatonin, though properly classified as a hormone as opposed to a neurotransmitter, is otherwise no exception to this rule. Melatonin levels in the GI tract routinely attain levels 10 to 100 times higher than the levels achieved in systemic circulation when melatonin is released by the pineal gland. The gut produces melatonin in response to food intake, where it seems to act locally without significantly altering the levels in systemic circulation. Unlike pineal melatonin, which is secreted directly into the bloodstream, gut melatonin is absorbed from the digestive tract into the portal circulation, where it is then subject to first-pass metabolism in the liver.
That being said, if melatonin levels after a meal are high enough that the liver cannot metabolize them completely, it would be expected that some melatonin could escape into systemic circulation and thereby cause drowsiness. This may actually explain why people commonly report feeling drowsy after an unusually large meal.
But as healthcare practitioners, it is more relevant to consider such questions as follows: what role does melatonin play in the gut, are there any disorders which might involve decreased melatonin production in the gut, and would melatonin have any value as a supplement to support gut health?
It is certain that melatonin is required for healthy digestive function. Breast milk has been found to contain melatonin, which, in light of the fact that the infant GI tract cannot at first produce melatonin on its own, suggests that melatonin plays a critical role in digestion.
Research has elucidated many of these critical functions:
- melatonin increases circulation to the gastric mucosa (an effect antagonized by its precursor serotonin)
- melatonin exerts a gastro-protective antioxidant effect
- melatonin diminishes visceral pain by reducing the sensitivity of nociceptive neurons in the GI tract
- melatonin enhances GI motility, helping to drive the digestive process
- melatonin decreases gastric acid production and increases gastrin and bicarbonate production
- through its effect on gastrin, melatonin increases the tone of the lower esophageal sphincter (LES)
Through a consideration of its functions above, melatonin would seem so intimately linked to disorders such as heartburn, gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), and even peptic ulcer disease that one might wonder whether a melatonin deficiency is not in fact the cause of these disorders.
This possibility has made melatonin the subject of considerable research, and so far the evidence supports the following conclusions:
- People suffering from heartburn and GERD have lowered GI melatonin levels[i]
- Melatonin can be more effective than proton pump inhibitors in treating GERD[ii]
- Melatonin accelerates the healing of gastric ulcers in rats[iii]
- Melatonin can improve symptoms of pain, bloating, and constipation in people with IBS[iv]
It is astounding that a natural molecule with so much potential has been ignored for so long. It is actually an embarrassingly common problem in science that the circumstances of something’s discovery will heavily bias the understanding of its function. Consider the amino acid asparagine, so named because it was initially discovered as a component of asparagus. We now know that asparagine is an integral component of millions of proteins throughout the domains of life, but the name stuck because that is where it was discovered.
Another example is the cytokine tumor growth factor beta, which is now known to have multiple, complex functions beyond that which became its namesake. Melatonin was first discovered in the pineal gland, where its secretion is inhibited by light, and as such it was named “the sleep hormone” and wrongfully presumed for a long time to possess only this limited function. Promoting the onset of sleep in the brain is just one of melatonin’s many functions, possibly even a minor one given its relatively staggering abundance elsewhere in the body.
Although there remains some suspicion about the long-term safety of melatonin supplements, including the possible effects of taking melatonin during the day, the evidence thus far does not suggest there is any harm in doing this. Studies have shown that taking melatonin as a supplement, even during the day for up to 45 days, produced no reported adverse effects in people with gastric reflux and produced only mild drowsiness as an adverse effect in healthy controls. Given the fact that patients with GERD have been shown to suffer from low melatonin levels and often suffer from co-morbid sleep problems, it makes sense that supplemental melatonin would not cause excessive drowsiness in such people, whereas it would in healthy controls (who may be presumed to already have normal melatonin levels).
There is also some concern that supplementing melatonin during the day might alter circadian rhythms and that this might theoretically raise concerns about cancer, though such concerns might be easily circumvented by supplementing melatonin exclusively at night.
Though correlational studies have shown that prolonged alteration of normal circadian rhythms, i.e., through shift work, may increase cancer risk, melatonin itself seems to limit tumor growth and enhance apoptosis to the extent that it has been explored as an experimental treatment for cancer and that the cancer epidemic itself is blamed in part on the overuse of artificial lighting, chronically lowering melatonin levels throughout the population. The fact that melatonin is routinely secreted during the day in most individuals, in response to daytime meals, might further allay concerns that this is harmful in the long term.
In conclusion, the more we learn about the complexities of the gastrointestinal tract, including the gut-brain axis, the more we may come to appreciate how simple lifestyle interventions, such as sticking to a normal sleep schedule, can profoundly affect a diverse range of very common health problems, especially such as pertain to the digestive tract. This also bespeaks the power of relatively simple dietary supplements to promote healthy digestion and support the functions of the digestive tract, in ways which may at first not seem intuitive. This is also why a sound knowledge of both normal physiology and pathophysiology is so crucial to the practice of medicine, whether one is treating with conventional drugs or natural alternatives.
It is noteworthy that benzodiazepines were once actually toyed with as a potential treatment for GERD, given their marked sedative effects and the close association between GERD and sleep problems. Such treatments did not prove to be effective, but perhaps they would have had better results had they employed a more natural sedative, say one which is naturally present in the gut and, indeed, integral to its function.
[i] Klupinska et al. Nocturnal Secretion of Melatonin in Patients with Upper Digestive Tract Disorders. Journal of Physiology and Pharmacology, 2006 Nov;57 Suppl 5:41-50. PMID: 17218759
[ii] Pereira, R. Regression of Gastroesophageal Reflux Disease Symptoms Using Dietary Supplementation with Melatonin, Vitamins, and Aminoacids: comparison with Omeprazole. Journal of Pineal Research, 2006 Oct;41(3):195-200. DOI: 10.1111/j.1600-079X.2006.00359.x
[iii] Majka J, Wierdak M, Brzozowska I, et al. Melatonin in Prevention of the Sequence from Reflux Esophagitis to Barrett’s Esophagus and Esophageal Adenocarcinoma: Experimental and Clinical Perspectives. International Journal of Molecular Sciences, 2018;19(7):2033. DOI:10.3390/ijms19072033
[iv] Chojnacki et al. Influence of Melatonin on Symptoms of Irritable Bowel Syndrome in Postmenopausal Women. Endocrynologia Polska, 2013;64(2):114-20. PMID: 23653274
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